Studies on the clinical pharmacology of biochemically specific antidepressants produce both therapeutic advances and increased knowledge concerning the biological basis of affective illness. Pharmacokinetic studies have focused on hydroxylation as the most clinically relevant metabolic paythway. We find that decreased hydroxylation among such genetically distinct populations as the Chinese may explain altered drug response. Aging is associated with decreased renal clearance of active hydroxy metabolites and decreased physiologic but not biochemical responses to tricyclic antidepressants. Further pharmacodynamic investigations reveal that five distinct antidepressant treatments - ECT, lithium clorgyline, desipramine and zimelidine, all ultimately reduced the turnover of norepinephrine and/or its major metabolites in man. The biochemical effects, however, are not sufficient for antidepressant action. Low dose clorgyline, a MAO-type A inhibitor, has proved to be a particularly effective antidepressant and specific for the noradrenergic system. Primate experiments support an iterpretation that rodent models identifying serotonin as a substrate for MAO-type A cannot be extrapolated to man.